The present invention relates to a series of new benzopyran derivatives which have an anti-hypertensive activity and can thus be used for the treatment and prophylaxis of cardiovascular diseases. The invention also provides methods and compositions using these compounds as well as processes for their preparation.
The compounds of the present invention are the 3,4-dihydro-2,2-dimethyl-4-(1-oxoisoindolin-2-yl)-6-perfluoroalkylsulfonyl -2H-1-benzopyran-3-ol compounds, the 3,4-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-6-trifluoromethyl sulfonyl-2H-1-benzopyran-3-ol compounds, nitrates of these compounds, analogs of these compounds having a carbon-carbon unsaturated bond at the 3,4-position of the pyran ring and derivatives of these compounds and their nitrates in which the isoindolinyl or pyridyl ring is substituted.
Certain compounds of this type and having this type of activity are disclosed in J. Med. Chem., 29, 2194 (1986), in European Patent Specifications No. 350 805, 273 262 and 314 446 (equivalent to U.S. Pat. No. 4,925,839), and in U.S. Pat. No. 4,908,378, and, of the compounds disclosed in the prior art references referred to here, the closest to the compounds of the present invention are disclosed in European Patent Specification No. 350 805 and U.S. Pat. No. 4,908,378 and are believed to be 6-cyano-3,4-dihydro-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl)-2H-1.benzopyran- 3-ol (which has the formula A given below), 3,4-dihydro-2,2-dimethyl-6-trifluoromethylsulfonyl-4-(2-oxo-1-pyrrolidinyl )-2H-1-benzopyran-3-ol (which has the formula B given below) and 3,4-dihydro-2,2-dimethyl-4-(1-oxoisoindolin-2-yl)-6-trifluoromethylsulfony l-2H-1-benzopyran-3-ol (which has the formula C given below): ##STR3##
The [(+)-6-cyano-3,4-dihydro-2,2-dimethyl trans-4-(2-oxo-1-pyrrolidinyl)-2H-1-benzopyran-3-ol isomer of Compound A, known as Cromakalim, is believed to be under investigation as a possible commercial vasodilating agent.
Although these prior compounds have acceptable and useful activities, their activities and, especially, duration of action are less than is considered desirable.
We have now surprisingly discovered a limited series of compounds which have a similar class of activity and which have a combination of a 1-oxoisoindolin-2-yl or 1,2-dihydro-2-oxo-1-pyridyl group at the 4.position and a perfluoroalkylsulfonyl group at the 6-position, and which, as a result, are more potent and have a longer duration of action.